Sleeve Gastrectomy Is Associated with Improved Systemic Redox Homeostasis in T2DM Through Ghrelin–GHSR Attenuation,POMC Neuronal Modulation,and CD4 + T Cell Metabolic Reprogramming

Abstract

Objective:

Sleeve gastrectomy (SG) improves obesity-associated type 2 diabetes mellitus (T2DM) beyond mere weight loss. We investigated whether SG enhances systemic metabolic homeostasis by suppressing the Ghrelin–growth hormone secretagogue receptor (GHSR) axis, remodeling hypothalamic pro-opiomelanocortin (POMC) neuronal activity, and reprogramming CD4⁺ T cell immunometabolism.

Methods:

Using a diet-induced T2DM mouse model undergoing SG or Sham surgery, we integrated bulk/single-cell RNA sequencing and metabolomics to evaluate systemic neuro-immune-metabolic alterations. Functional assays validated Ghrelin’s effects on CD4⁺ T cell metabolism and differentiation, alongside assessments of hepatic/pancreatic function and hypothalamic neuronal activity.

Results:

SG globally remodeled peripheral immunity, expanding Tregs while reducing pro-inflammatory Th17 cells. scRNA-seq and metabolomic profiling revealed that CD4⁺ T cells shifted metabolically from glycolysis toward oxidative phosphorylation, matching increased tricarboxylic acid cycle intermediates. Functionally, Ghrelin–GHSR signaling promoted CD4⁺ T cell glycolysis, mitochondrial damage, and Th17 skewing; GHSR antagonism successfully reversed these detrimental effects. Systemically, SG reduced hyperglycemia and hepatic lipidosis, restored islet α/β-cell balance, activated anorexigenic POMC neurons, and suppressed AgRP neurons.

Conclusion:

SG alleviates T2DM through coordinated suppression of the Ghrelin–GHSR axis, bridging central appetite regulation with peripheral immunometabolic reprogramming. By shifting CD4⁺ T cells toward oxidative metabolism and restoring the Treg/Th17 balance, SG drives systemic metabolic recovery, providing critical molecular insights into the neuro-immune mechanisms of metabolic surgery. Antioxid. Redox Signal. 00, 000–000.